Improving enteral nutrition tolerance and protein intake maybe beneficial to intensive care unit patients

Enteral nutrition (EN) is important for critically ill patients. This study investigated the current situation of EN treatment in SHANGHAI intensive care units (ICUs). We hypothesized that improving EN practice in SHANGHAI may benefit the prognosis of ICU patients. Clinical information on EN use was collected using clinic information forms in 2019. The collected data included the patient’s general clinical information, EN prescription status, EN tolerance status, and clinical outcomes. The observation time points were days 1, 3, and 7 after starting EN. A total of 491 patients were included. The proportion of EN intolerance (defined as < 20 kcal/kg/day) decreased, with rates of intolerance of 100%, 82.07%, 70.61%, and 52.23% at 1, 3, 7, and 14 days, respectively. Age, mNutric score, and protein intake < 0.5 g/kg/day on day 7 were risk factors for 28-day mortality.The EN tolerance on day 7 and protein intake > 0.5 g/kg/day on day 3 or day 7 might affect the 28-day mortality. Risk factors with EN tolerance on day 7 by logistic regression showed that the AGI grade on day 1 was a major factor against EN tolerance. The proportion of EN tolerance in SHANGHAI ICU patients was low. Achieving tolerance on day 7 after the start of EN is a protective factor for 28-day survival. Improving EN tolerance and protein intake maybe beneficial for ICU patients.


Study design
This observational study included consecutive patients from the ICUs of 15 hospitals in SHANGHAI admitted from January to December 2019.The clinical data were collected according to the designed case report form.This study was approved by the Ethics Committee of our Hospital.As the major purpose is to the relation between EN tolerance and survival in ICU, this is made in a perspective way.

Study population Inclusion criteria
(1) Patients admitted to the ICU of 15 hospitals who consented and agreed to participate in this research.

Data collection
The patient's information was recorded in a case information sheet that included: (1) Nutritional risk assessment: NRS2002 score and mNutric score on ICU admission.
(2) Nutrition prescription (days 1, 3, 7, and 14 after ICU admission): the actual calorie of EN and parenteral nutrition (PN), the amount of protein and amino acid.(3) Data related to EN tolerance (days 1, 3, 7, and 14 after ICU admission): actual calorie and protein intake, AGI score, and gastrointestinal symptoms.EN tolerance was defined as the caloric supply of the patient reaching 20 kcal/kg/day within 72 h from the start of EN 5,6 .The symptoms of FI defined according to the judgement of ICU physician or ESICM Working Group on Abdominal Problems 5 .(4) Patients' outcomes: 28-day mortality and in-ICU mortality.
As for ICU patients who were transferred out earlier than the time point, the laboratory indicators, AGI grade, the amount of calories and protein, organ support, and other items at the time point were analyzed according to the data on the day of transfer.

Statistical analysis
All data were tested for normal distribution.The continuous data not conforming to the normal distribution were expressed as median (interquartile range, IQR).Nonparametric tests were used to compare the two groups.The categorical variables were described as n (%) and analyzed using the chi-square test or Fisher's exact test.Univariable logistic regression was used for risk factor screening; variables with P-values < 0.05 were included in the multivariable logistic regression for further validation.The survival analysis was performed using the Kaplan-Meier method, and the curves were compared using the log-rank test.COX regression also used for survival.SPSS 22.0 (IBM Corp.) was used for statistical analysis in this study.Two-sided P-values < 0.05 were considered statistically significant.The Cochran-Armitage Trend Test was conducted to test the trend in categorical variables.Jonckheere-Terpstra test is used to determine whether two or more independent samples are derived from the same distribution.The Mantel-Haenszel Test is used to analyze the association between two categorical variables, taking into account the influence of one or more stratified variables.

Ethical approval
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Ruijin Hospital of Shanghai Jiaotong University School of Medicine, China (Project identification code

The effect of EN intake on the survival of ICU patients
Taking the 28-day survival status as the endpoint, the comparison between EN reached 20 kcal/kg/day on day 3 was listed (Table S2).The survival rate was no significant difference.However, Kaplan-Meier survival analyses were performed on whether calories reached 20 kcal/kg/day on day 3 (Fig. 2A or day 7 (Fig. 2B) of ICU admission.The results showed that the survival curve of patients with EN tolerance on day 7 of ICU admission was better than in patients with intolerance (P = 0.01), while there were no differences on day 3 (P = 0.2).The Cox regression shows the same patten: Day 3 p = 0.09, HR 0.83 95% CI (0.67,1.03),Day 7 p = 0.04, HR 0.82 95% CI (0.75,0.98).We adjusted age and ApacheII score in COX regression model.

The effect of protein intake on the survival of ICU patients
Using the 28-day survival status as the endpoint, the comparison between whether the protein reached 0.5 g/kg/ day on day 3 on day 3 or not was listed (Table S2).The survival rate was no significant difference.Kaplan-Meier survival analyses were performed on whether the protein reached 0.5 g/kg/day on day 3 (Fig. 2C) and day 7 (Fig. 2D) of ICU admission.The results showed that the survival curve of patients whose protein intake reached 0.5 g/kg/day on days 3 and 7 was better than those who did not reach 0.5 g/kg/day (Day3 P < 0.01, Day 7 P < 0.01).

Influencing factors of EN intake in ICU patients on day 7
The factors that might influence EN tolerance were included in a logistic regression to analyze EN tolerance in ICU patients on day 7. Preliminary analysis by univariable logistic regression showed that the AGI grade on day 1 (OR = 0.53), the use of organ support on day 3 (OR = 1.80), and the subjective judgment of the physician on EN tolerance on day 3 (OR = 2.96) were statistically significant.We take those factors above (they are with statistically significant in univariable regression) to making multivariable logistic regression, it was found that the AGI grade on day 1 (OR = 0.46) and the use of any organ support on day 3 (OR = 2.08) had a significant impact on EN tolerance in critically ill patients on day 7 (Table 3).

Discussion
In this study, we collected clinical information in critically ill patients admitted to the ICUs in 15 hospitals in SHANGHAI.Our data suggest that enteral nutrition tolerance and adequate protein intake are important for improving survival in ICU patients, as we hypothesized.

Nutritional assessment
Nutritional status and risk of malnutrition should be assessed first before nutritional treatment.Heyland 7 And Jie 8 conducted prospective non-randomized studies that showed that patients with high malnutrition risk were more likely to benefit from early EN.The NRS2002 and Nutric assessments are the most recommended assessment methods.It is necessary to emphasize that there are still controversies regarding the best tool for assessing the malnutrition risk 6 .Therefore, further research is needed to find more reasonable ways to evaluate the nutritional status of critical patients.

Use of PN
In this study, 59.47% of the patients started PN at ICU admission, while 43.58% on day 3 and 38.69% on day 7.These results agree with Xing et al. 9 , suggesting that PN was started earlier in ICU patients in China.It is currently believed that PN should be the rescue remedy for EN.Nevertheless, compared with EN, the implementation and monitoring of PN is relatively simple, and it is easy to achieve the nutritional goals, which fits the situation of insufficient ICU resources in China 10 .The NUTRIREA-2 study showed 11 that patients with full PN developed significantly fewer gastrointestinal symptoms, and PN did not increase the mortality rate and incidence of nosocomial infection.

Calories and protein target setting and EN tolerance
Indirect calorimetry (IC) is considered the gold standard for calorie target setting in the ICU so as to prevent underfeeding and overfeeding [12][13][14] .In this study, the target calorie and protein were mainly calculated according to the guidelines, accounting for 56.82% of the cases.This is reasonable to use a metabolic formula since none of the centers in this study is equipped with IC.The recommendations for calculating target energy differ between guidelines 15,16 .According to the ASPEN recommendation, the target calorie in our population was estimated to be 1350-1650 kcal/kg/day (the median weight was 65 kg), similar to the target calorie set by clinicians in the actual practice.In this study, patients reaching 20 kcal/kg/day on day 3 did not show benefit on survival.Several studies 12, 17-19 reported a higher need for organ support in full-energy supply patients than in underfed patients.The time of reaching the target calorie is controversial.It is believed that endogenous energy is produced in the acute stage, and nutrition support may lead to harmful overfeeding to patients 20 .An observational study found that meeting 70-80% of the target calorie within 1 week might be ideal 21 .Notably, the EN formulation used in this study was mostly 1 or 0.9 kcal/ml.Meeting the target energy intake requires about 1300 ml of EN, which increases the difficulty of fluid management in critically ill patients and might be unfavorable for the removal of organ support such as mechanical ventilation or renal replacement therapy.Meanwhile, on day 7, EN intake < 20 kcal/ kg/day (intolerance) was happened in 70% patients, with the negative impact on 28-day survive (Kaplan-Meier survival analysis).This result is concordance with other reports 10,11,15,16 , which reference the benefit to reaching EN tolerance within 7 days.
It is widely accepted that the protein intake in critically ill patients should be > 1 g/kg/day and at least 0.8 g/ kg/day for general hospitalized patients 22,23 .In this study, only about 50% of patients reached an intake of > 0.5 g/ kg/day.In the NEED study by Ke et al. 24 , the average protein intake was 0.67 g/kg/day.In this study, logistic regression and the Kaplan-Meier survival analysis indicated that a protein intake < 0.5 g/kg/day on day 3 or 7 significantly affected 28-day mortality.These results are supported by other observational studies 25,26 , emphasizing the importance of protein intake in the early stage of critical illness.Obviously, improving EN tolerance is helpful to reach the protein target.

Risk factors of EN intolerance
An international nutrition survey showed that the average calorie intake in critically ill patients on day 7 was at 16.5 kcal/kg/day 27 .The 2017 Nutrition Day survey also showed that less than 25% of the patients reached a target volume of 25 kcal/kg/day within 2 weeks in the ICU 28 .According to the definition of EN intolerance, it is sure that most patients could be diagnosed with EN intolerance.FI can also be diagnosed based on symptoms such as abdominal distension, nausea and vomiting, and gastric residual volume (GRV).Taking routine GRV measures is against the mainstream guidelines, while other symptoms lack an objective way of quantification 15,16 .Using the actual feeding amount as the criterion for EN intolerance is more relative to the EN intolerance definition, and the method is objective and easy to standardize.Therefore, we defined EN intolerance according to whether the EN could reach 20 kcal/kg/day.
In this study, the main factors predicting EN tolerance on day 7 were AGI grade on day 1 and any organ support on day 3.A study showed that the AGI grade on day 1 was associated with future GI function and ICU outcomes 29 .The intestinal function of critically ill patients can often be improved after appropriate treatment and organ support (mechanical ventilation, renal replacement therapy, vasopressor, etc.).Thus, organ support means a higher probability of controlling the critical state, so there might be a higher possibility that the GI function could be preserved.The predictors of EN tolerance are less studied because of the significant differences in the definition of EN tolerance, especially when tolerance is judged according to the symptoms 4 .Hu et al. 4 reported that 15 factors, including pneumonia, nutritional preparation, shock, skin infection, continuous feeding, etc., were associated with tolerance and established a predictive model.Unfortunately, the number of patients was small, and the results need to be confirmed 4 .
In this study, 15.01%(n = 94) of patients received post-pyloric feeding in the ICU, which is a low level.Postpyloric feeding can improve EN tolerance and thus improve nutritional intake 24 , but the regression analysis in this study showed that the use of post-pyloric feeding did not affect whether the patient's calorie intake reached 20 kcal/kg/day.

Limitations
This study has limitations.First, as an observational study, the causal relationship between EN treatment and the patient outcome cannot be established.Secondly, the number of hospitals involved in this study was less than half of the number of tertiary hospitals in SHANGHAI and did not cover the secondary hospitals, thus biasing the results.In addition, although this study included consecutive patients admitted over 1 month in 15 ICUs, the sample size was relatively small.Third, the study time in each center was about 1 month, and no further longterm prognosis of the patients was followed up.The impact of nutritional therapy on patients might be difficult to reflect on in the short term, and follow-up for long-term outcomes is necessary.
The institutions that participated in the study covered half of the city districts (8/16 districts in SHANGHAI) and were mainly tertiary hospitals that admitted patients from all over SHANGHAI.Thus, we believe the patients' data are representative of the SHANGHAI ICU patients.

Figure 1 .
Figure 1.The flowchart about inclusion and exclusion.

Table 1 .
General characteristics of patients.

Table 3 .
Logistic regression on the relationship between patients' characteristics and EN tolerance (> 20 kcal/kg/day) on Day 7. *P < 0.05, all those factors with p < 0.05 in univariable regression was adjusted in multivariable logistic regression.EN Enteral nutrition.